Strong therapeutic potential of γ-secretase inhibitor MRK003 for CD44-high and CD133-low glioblastoma initiating cells

• Published in: Journal of neuro-oncology 2015-01, Vol.121 (2), p.239-250
• Main Authors: Tanaka, Shingo, Nakada, Mitsutoshi, Yamada, Daisuke, Nakano, Ichiro, Todo, Tomoki, Ino, Yasushi, Hoshii, Takayuki, Tadokoro, Yuko, Ohta, Kumiko, Ali, Mohamed A. E., Hayashi, Yutaka, Hamada, Jun-ichiro, Hirao, Atsushi
• Format: Article
• Language: English
• Subjects: AC133 Antigen; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Antigens, CD - metabolism; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - physiology; Biomarkers, Tumor - metabolism; Cell Survival - drug effects; Cell Survival - physiology; Cyclic S-Oxides - pharmacology; Dose-Response Relationship, Drug; Glioblastoma - drug therapy; Glioblastoma - physiopathology; Glycoproteins - metabolism; Humans; Hyaluronan Receptors - metabolism; Inhibitory Concentration 50; Laboratory Investigation; Medicine; Medicine & Public Health; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - physiology; Neurology; Oncology; Peptides - metabolism; Protease Inhibitors - pharmacology; Spheroids, Cellular - drug effects; Spheroids, Cellular - physiology; Thiadiazoles - pharmacology; Tumor Cells, Cultured
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1007/s11060-014-1630-z

The Notch signal regulates both cell viability and apoptosis, and maintains stemness of various cancers including glioblastoma (GBM). Although Notch signal inhibition may be an effective strategy in treating GBM initiating cells (GICs), its applicability to the different subtypes of GBM remains unclear. Here, we analyzed the effectiveness of MRK003, a preclinical γ-secretase inhibitor, on GICs. Nine patient-derived GICs were treated by MRK003, and its efficacy on cell viability, apoptosis, sphere forming ability and Akt expression level which might be related to Notch downstream and be greatly important signals in GBM was evaluated. MRK003 suppressed viability and sphere-formation ability, and induced apoptosis in all GICs in varying doses of MRK003. Based on their sensitivities to MRK003, the nine GICs were divided into “relatively sensitive” and “relatively resistant” GICs. Sensitivity to MRK003 was associated with its inhibitory effect on Akt pathway. Transgenic expression of the myristoylated Akt vector in relatively sensitive GICs partially rescued the effect of MRK003, suggesting that the effect of MRK003 was, at least in part, mediated through inhibition of the Akt pathway. These GICs were differentiated by the expression of CD44 and CD133 with flow cytometric analysis. The relatively sensitive GICs are CD44-high and CD133-low. The IC 50 of MRK003 in a set of GICs exhibited a negative correlation with CD44 and positive correlation with CD133. Collectively, MRK003 is partially mediated by the Akt pathway and has strong therapeutic potential for CD44-high and CD133-low GICs.